Purpose To develop a weakly supervised deep learning (WSDL) method that could utilize incomplete/missing survival data to predict the prognosis of extranodal natural killer/T cell lymphoma, nasal type (ENKTL) based on pretreatment 18F-FDG PET/CT results. Methods One hundred and sixty-seven patients with ENKTL who underwent pretreatment 18F-FDG PET/CT were retrospectively collected. Eighty-four patients were followed up for at least 2 years (training set = 64, test set = 20). A WSDL method was developed to enable the integration of the remaining 83 patients with incomplete/missing follow-up information in the training set. To test generalization, these data were derived from three types of scanners. Prediction similarity index (PSI) was derived from deep learning features of images. Its discriminative ability was calculated and compared with that of a conventional deep learning (CDL) method. Univariate and multivariate analyses helped explore the significance of PSI and clinical features. Results PSI achieved area under the curve scores of 0.9858 and 0.9946 (training set) and 0.8750 and 0.7344 (test set) in the prediction of progression-free survival (PFS) with the WSDL and CDL methods, respectively. PSI threshold of 1.0 could significantly differentiate the prognosis. In the test set, WSDL and CDL achieved prediction sensitivity, specificity, and accuracy of 87.50% and 62.50%, 83.33% and 83.33%, and 85.00% and 75.00%, respectively. Multivariate analysis confirmed PSI to be an independent significant predictor of PFS in both the methods. Conclusion The WSDL-based framework was more effective for extracting 18F-FDG PET/CT features and predicting the prognosis of ENKTL than the CDL method.

Intracranial hemorrhage remains the most feared complication in tissue plasminogen activator (tPA) thrombolysis for ischemic stroke. However, the underlying molecular mechanisms are still poorly elucidated. In this study, we reported an important role of caveolin-1 (Cav-1) s-nitrosylation in matrix metalloproteinase (MMP)-2 and 9 secretion from tPA-treated ischemic endothelial cells. Brain vascular endothelial cells (bEND3) were exposed to oxygen-glucose deprivation (OGD) for 2 h before adding recombinant human tPA for 6 h. This treatment induced a significant increase of MMP2 and 9 in the media of bEND3 cells and a simultaneous degradation of fibronectin and laminin β-1, the two main components of extracellular matrix (ECM). Inhibition of MMP2 and 9 with SB-3CT completely blocked the degradation of fibronectin and laminin β-1. ODG+tPA treatment led to Cav-1 shedding from bEND3 cells into the media. Notably, OGD triggered nitric oxide (NO) production and S-nitrosylationof Cav-1 (SNCav-1). Meanwhile tPA induced activation of ERK signal pathway and stimulates the secretion of SNCav-1. Pretreatment of bEND3 cells with C-PTIO (a NO scavenger) or U0126 (a specific ERK inhibitor) significantly reduced OGD-induced S-nitrosylation of Cav-1 in cells and blocked the secretion of Cav-1 and MMP2 and 9 into the media as well as the degradation of fibronectin and laminin β-1 in OGD and tPA-treated cells. These data indicate that OGD-triggered Cav-1 S-nitrosylation interacts with tPA-induced ERK activation to augment MMP2 and 9 secretion and subsequent ECM degradation, which may account for the exacerbation of ischemic blood brain barrier damage following tPA thrombolysis for ischemic stroke.

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Background: To investigate the protective efficacy of miR-155 on down regulating NADPH oxidase isoform subunit A1 (NoxA1) gene expression, resulting in inhibition of VSMC migration and over proliferation and thus ameliorating the progression of arterial atherosclerosis in AS mouse model. Therefore, to further explore the regulatory effect of miR-155 on neointima formation in AS and locate potential antiatherosclerosis target. Methods: The mouse vascular aorta smooth muscle cell (MOVAS) was cultured and transfected with recombinant Pad2YFG adenovirus fluorescent vector with miR-155 fragment into 4 groups. Western blotting and RT-PCR were performed to identify the expression of NoxA1 under different circumstances. Fluorescence microscope was applied to observe the transfection rate of miR-155 into adenovirus. Twelveweek fatty food induced atherosclerotic ApoE −/− mouse model was established as host to accept miR-155 transfected adenovirus transplantation to observe its effect on VSMC in AS progression. Carotid and thoracic artery were extracted at 1 month after dosing. Distribution of miR-155 was quantified via expression levels of protein and RNA to detect NoxA1, Nox1, p47phox and NADPH expression. Immunohistochemistry, fluorescence imaging and other methods were performed in arteries section to compare the thickness of neointima and assess the severity of AS in each group.Results: Luciferase reporter gene assay showed significant expression of miR-155 in mimic group indicating that miR-155 had target binding effect with NoxA1 gene. Western blotting and RT-PCR results both showed significantly decreased NoxA1 expression in miR-155 mimic group while increased with its inhibitor. The miR-155 distribution was observed varied at 1 month after in control, miR-155 mimic and inhibitor groups. The NoxA1, NADPH, Nox1 and pp47phox protein expression in VSMC was decreased in mimic group vs control and inhibitor groups (P<0.05); no significant difference of NADPH expression was observed in all groups. The NoxA1, Nox1 and p47phox gene expression in VSMC were both found reduced compared with those of control group at week 4 (P<0.05). Immunohistochemistry staining of artery frozen sections figured out that the thickness of neointima of carotid artery in miR-155 mimic group was significantly lower vs control and inhibitor groups (P<0.01) at week 4.Conclusions: miR-155 played an important role in NoxA1-related signaling pathway. miR-155 transfection into VSMC may have anti-inflammatory regulatory effect on NoxA1 expression in vivo and resulting in amelioration of atherosclerotic lesion in AS mouse model. In summary, miR-155 specifically plays in a negative feedback loop and demonstrates a protective role during atherosclerosis-associated VSMC proliferation and neointima formation through the miR-155-NoxA1-p47phox complex signaling pathway.